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patented or. 18 1947 UNITED STATES PATENT OFFICE 1;2,3,4 TETBAHYDRO6-ALKOXY-8* (OMEGA- DIALKYL-AMINO-ALKYL-AMINO) QUINO- LINES AND METHOD FOR THEIR PREP- ARATION Harry James Barber, Gidea Park, and William Robert Wragg, Cockfosters, England, assignors to May & Baker Limited, Dagenham, England,

a British company No Drawing. Application March 14, 1944, Serial No. 526,474. In Great Britain March 1, 1943 Formula I HNCH(CHz)aN Formula 2 EN C H2) 3N CzHg Formula 3 CzHs Formula 4 A disadvantage of these compounds when used as antimalarial agents is that they exhibit substan- 11 Claims. (Cl. 260288) 2 tial toxicity toward the human organism, a factor of great importance in view of the long periods of treatment and relatively large dosages necessary to control the protozoan infection.

It is now found, pursuant to the present invention, that a class of related compounds possesses antimalarial activity comparable to the quinoline derivatives above mentioned but the compounds, unexpectedly, have materially reduced toxicity. These new compounds are 122:3:4-tetrahydro-G-alkoxy-S- (omega-dialkylamino-alkyl amino) -quinolines which can be represented by the general formula wherein R1, R2, and R3 are lower alkyl groups and a: is an integer less than 10. Examples are 1:2:324 tetrahydro-G-methoxy-S-(omega dial kylamino-propylamino) -quino1ines, 1 :2 :3 :4-tetrahydro-6-methoxy-8-(omega dialkylamino-butylamino) -quinolines and 1 :2 :3 :4-tetrahydro-6- methoxy-8-(omega-dialkylamino isopentylami no)-quinolines, specifically the B-(omega-diethylamino-propylamino), the 8-(omega-diethylamino-butylamino), and the 8-(omega-diethy1amino-isopentylamino) compounds.

These now compounds can be prepared in accordance with the present invention by reduction of the corresponding quinoline derivatives using catalytic hydrogenation, preferably with Raney nickel, or by chemical or electro-chemical methods of reduction which are conventional for the quinoline series.

It is also contemplated within the present invention to prepare these novel compounds by methods heretofore employed in manufacture of the corresponding quinoline compounds, with substitution of a tetrahydroquinoline intermediate for the corresponding quinoline intermediate.

The invention further includes preparation of these new compounds by alkaline or neutral reduction of the anils obtained by condensation of 6-alkoxy-8-amino-quinoline with a ketal of an omega-dialkylamino-a1kanone, for instance a suitable ketal of omega-diethylamino-pentanone- 2. This reduction can be effected satisfactorily by use of metallic sodium in essentially anhydrous alcoholic solution. Thus, for example, sodium in ethyl or amyl alcohol can be employed. Anhydrous conditions are necessary because the anils are sensitive to hydrolysis.

Another process within the purview of the present invention for preparing these novel compounds comprises the reaction of 1:2:3z4-tetrahydro-6-alkoxy-S-amino-quinolines in the presence of ammonium chloride or other slightly acidic salt with a compound having one of the following formulae:

wherein R and R4 are lower alkyl groups or hydrogen atoms, R1, R2 and R3 are lower alkyl groups, and n is an integer more than 2 and less than 10, followed by reduction of the reaction products thus obtained. Catalytic hydrogenation or reduction with sodium in alcohol (for example, ethyl or amyl alcohol) are satisfactory methods for this purpose.

It should be understood that the designations (CHzM and (CHz)n-1 used in this specification and in the appended claims include not only straight chain but also branched chain alkyl groups.

The following examples illustrate methods of carrying out the present invention, but it is to be understood that these examples are given by way of illustration and not of limitation;

Example I About 174 gm. of S-methoxy-B-amino-quinoline are reduced catalytically in the presence of 20% Raney nickel at 120 C. and 35 atmospheres pressureusing 200 cc. dioxane as solvent. The product, 6-methoxy-8-amino 1:2:3z4 tetrahydroquinoline, is distilled (B. P. 19D/3 mm.) and stored in an atmosphere of hydrogen.

About 17.8 gm. of fi-methoxy-S-amino-l:2z3z4- tetra-hydroquinoline thus prepared, 25.0 gm. of omega-diethylamino-p,e-di-ethoxy-pentane and approximately 0.2 gm. of ammonium chloride (as catalyst) are heated at a uniform rate from 135 C. to 195 C. over 2 hours with stirring. Practically the theoretical quantity of alcohol is evolved. The product is vacuum distilled, the fraction B. P. 184/.1 mm. which consists of 6- methoxy-B-N(-omega-diethylamino o: methylbutylidene) -amino-1 2 3 l-tetra-hydroquinoline, is stored in an atmosphere of hydrogen.

About 10 gm. of G-methoxy-fl-N (omega-diethylamino a methyl-butylidene) amino-1:2:3z4- tetrahydroquinoline obtained in this manner are thee s elvs n 9. 9- Q anhyd us et l we:

4 hol in an atmosphere of hydrogen. Approximately 4.5 gm. of sodium are added in small pieces over 1 hour, the reaction being completed by heating on a steam bath under reflux. The prodnot is made acid with concentrated hydrochloric acid, warmed to decompose unreduced anil, filtered to remove salt and the alcohol distilled from the filtrate under reduced pressure. The filtrate is then made basic and extracted with ether.

After evaporation of the other the product is distilled in an atmosphere of hydrogen and a fraction B. P, 175180/.1 mm. 6-methoxy-8-N (omega-diethylamino-a-methyl-butyl) amino- 1:2:3: l-tetrahydroquinoline, is collected. The product is stored in an atmosphere of hydrogen.

Example II 200 gm. of fi-methoxy-S-aminoquinoline is reduced catalytically in the presence of 18% Raney nickel at C. and 40 atmospheres pressure using 200 c. c. dioxane as solvent. The product, 6-methoxy-8-amino- 1 t 2 3 z l-tetrahydro quinoline (B. P. l35/0.05 mm., 95% yield) is stored in an atmosphere of hydrogen.

A mixture of 84.5 gm. of 1:2:3z-tetrahydro-6- methoxy-S-aminoquino-line, gm. of 5diethylamino-2:Z-diethoxypentane and 1.5 gm. of ammonium chloride are heated at -170 C. for 1 hour and then at ITO- C. for hour with vigorous stirring, in an atmosphere of hydrogen. Practically the theoretical quantity of alcohol is evolved. The reaction product, mainly G-methoxy- B-N-(Qmega diethylamino-a-methyl butylidene) amino l:2:3:4-tetrahydroquinoline is poured quickly into 3 litres of absolutely anhydrous amyl alcohol at 80 0., to which 40 gm. of sodium has just previously been added. IA further 120 gm. of sodium is then added and the alcohol refluxed until all the sodium has dissolved. An atmosphere of hydrogen is maintained over the reaction mixture during the following operations. The reaction mixture is made acid to Congo red with concentrated hydrochloric acid and the amyl alcohol removed by steam distillation. The liquors remaining are basified with 50% caustic soda and ether extracted] On removal of the ether the product is carefully fractionated. The fraction, B. P. l'75-l80/0.05 mm., B-methOXy-B-N-(Omega diethylamino-a-methyl butyl) amino-1: 2 :3 4- tetrahydro quinoline, in 74% yield, is stored in an atmosphere of hydrogen.

Example III 36 gm. of G-methoxy-S-N-(omega diethylamino-a-methyl butyD-amino quinoline is refiuxed with 1.3 litres of anhydrous amyl alcohol and 100 gm. of sodium until all the sodium has dissolved. The reaction scheme may be indicated thus:

An atmosphere of hydrogen is maintained over the reaction mixture during the following operations. The reaction is made acid to Congo red with concentrated hydrochloric acid and theamyl eehel r t eve by te m dist l tion, The

present invention without departing from the spirit and scope thereof and the invention is to be limited only by the appended claims.

What is claimed is:

1. A composition of matter represented by the formula:

wherein R1, R2 and R3 are of the class consisting of lower alkyl groups and :c is an integer less than 10.

2. A 1 :2 3 4-tetrahydro-6-a1koxy-8- (omegadialkyl-amino-alky1amino) -quinoline,

3. A 1 2 :3 4-tetrahydro-6-methoXy-8- (omegadialkyl-amino-propylamino) -quin0line.

4. A 1:2: :e-tetrahydro-fi-methoxy-8-(omegadialkyl-amino-butylamino) -quino1ine.

5. A 1 2 3 :4-tetrahydro-6-methoxy-8- (omegadialkyl-amino-isopentylamino) -quinoline.

6. 1:213:4-tetrahydro 6 methoxy-8-(omegadiethyl-amino-propylamino) -quino1ine.

7. 112:3:4-tetrahydro 6 methoXy-8-(omegadiethyl-amino-butylamino) -quino1ine.

8. 1 :2 23:4 tetrahydro-G-methoxy-S-(or-methyl omega-diethy1-amino-butylamino) -quinoline.

9. The process that comprises the step of reacting a 6-alkoxy-8-amino-quinoline with a substance selected from the class consisting of compounds of the formulae:

wherein R and R4 are of the class consisting of lower alkyl and hydrogen, R1, R2, and R3 are lower alkyl, and n is an integer more than 2 but less than 10; and reducing the reaction product to obtain a 1:2:3: i-tetrahydro-G-alkoxy- 8- (omega-dialky1amino-alkylamino) -quinoline.

10. The process that comprises condensing a G-alkoxy-S-amino-quinoline with a ketal of an omega-dialkylamino-alkanone to form an anil intermediate, and reducing this anil intermediate under anhydrous conditions to produce the corresponding 1 :2 3 i-tetrahydro-G-alkoxy-B- (omega-dialkylamino-alkylamino) -quinoline.

11. The process that comprises the following steps: catalytically reducing S-methoxy-B-aminoquinoline to produce 122:3:4-tetrahydro-6- methoXy-B-amino quinoiine, reacting the reduction product with omega-diethy1amino-p-,B-di ethoxy-pentane to produce 1:2:324-tetrahydro-6- methoxy 8 (a methyl omega diethylaminobutylideneamino)-quinoline, and reducing the reaction product to obtain 1:2:314-tetrahydro-6- methoxy-8-u-methyl-omega-diethylamino-butylamino) -quinoline.

HARRY JAMES BARBER. WILLIAM ROBERT WRAGG.

REFERENCES CITED The following references are of record in the file of thispatent:

UNITED STATES PATENTS Journal of The Indian Chemical Society, vol. 14, pages 468-473 (1937) Number 

